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Understanding Innate Immunity and Inflammation in Chapter 6 - Key Defense Mechanisms Explained

Explore the essential concepts of innate immunity and inflammation, including physical, mechanical, and biochemical barriers, the inflammatory response, and cellular mediators. Learn about the plasma protein systems, mast cells, and cellular processes involved in defense against pathogens and injury. Discover the roles of histamines, leukotrienes, prostaglandins, and more in the immune system's defense mechanisms. Gain insights into phagocytosis, the process by which cells ingest and eliminate foreign materials. Delve into the intricate workings of the immune system's first, second, and third lines of defense.

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Understanding Innate Immunity and Inflammation in Chapter 6 - Key Defense Mechanisms Explained

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  1. Innate Immunity: Inflammation Chapter 6

  2. Immunity • First line of defense • Innate resistance – physical (skin/epithelial layer, GI & Resp Tract), , mechanical (Cough, sneeze, vomit, cilia action in trachea) & biochemical barriers (antimicrobial peptides, lung secretions, mucus, saliva, tears, earwax) • Second line of defense • Inflammation – vascular response – dilation, histamines increase vessel leakage, wbc action, cytokines, leucokines, fever. Usually redness and heat with swelling. • Third line of defense • Adaptive (acquired) immunity – antibody production

  3. First Line of Defense • Physical and mechanical barriers • Skin • Linings of the gastrointestinal, genitourinary, and respiratory tracts • Sloughing off of cells • Coughing and sneezing • Flushing • Vomiting • Mucus and cilia

  4. First Line of Defense • Biochemical barriers • Synthesized and secreted saliva, tears, earwax, sweat, and sebum • Antimicrobial peptides • Cathelicidins, defensins, and collectins • Normal bacterial flora

  5. Second Line of Defense • Inflammatory response • Caused by a variety of materials • Infection, mechanical damage, ischemia, nutrient deprivation, temperature extremes, radiation, etc. • Local manifestations • Vascular response • Blood vessel dilation, increased vascular permeability and leakage, white blood cell adherence to the inner walls of the vessels and migration through the vessels

  6. Inflammation • Goals • Limit and control the inflammatory process • Prevent and limit infection and further damage • Interact with components of the adaptive immune system • Prepare the area of injury for healing

  7. Plasma Protein Systems • Protein systems • Complement system • Coagulation system • Kinin system • All contain inactive enzymes (proenzymes) • Sequentially activated • First proenzyme is converted to an active enzyme • Substrate of the activated enzyme becomes the next component in the series

  8. Plasma Protein Systems • Complement system • Can destroy pathogens directly • Activates or collaborates with every other component of the inflammatory response • Pathways • Classical • Lectin • Alternative

  9. Plasma Protein Systems • Coagulation (clotting) system • Forms a fibrinous meshwork at an injured or inflamed site • Prevents the spread of infection • Keeps microorganisms and foreign bodies at the site of greatest inflammatory cell activity • Forms a clot that stops bleeding • Provides a framework for repair and healing • Main substance is an insoluble protein called fibrin

  10. Plasma Protein Systems • Kinin system • Functions to activate and assist inflammatory cells • Primary kinin is bradykinin • Causes dilation of blood vessels, pain, smooth muscle contraction, vascular permeability, and leukocyte chemotaxis

  11. Plasma Protein Systems

  12. Plasma Protein Systems

  13. Cellular Mediators of Inflammation • Cellular components • Granulocytes, platelets, monocytes, and lymphocytes • Cell surface receptors • Pattern recognition receptors (PRRs) • Pathogen-associated molecular patterns (PAMPs) • Toll-like receptors • Complement receptors • Scavenger receptors

  14. Mast Cells • Cellular bags of granules located in the loose connective tissues close to blood vessels • Skin, digestive lining, and respiratory tract • Activation • Physical injury, chemical agents, immunologic processes, and toll-like receptors • Chemical release in two ways • Degranulation and synthesis of lipid-derived chemical mediators

  15. Mast Cell Degranulation • Histamine • Vasoactive amine that causes temporary, rapid constriction of the large blood vessels and the dilation of the postcapillary venules • Retraction of endothelial cells lining the capillaries • Receptors • H1 receptor (proinflammatory) • H2 receptor (anti-inflammatory)

  16. Histamine • Receptors • H1 receptor • Proinflammatory • Present in smooth muscle cells of the bronchi • H2 receptor • Anti-inflammatory • Present on parietal cells of the stomach mucosa • Induces the secretion of gastric acid

  17. Mast Cell Degranulation • Chemotactic factors • Neutrophil chemotactic factor • Attracts neutrophils • Eosinophil chemotactic factor of anaphylaxis (ECF-A) • Attracts eosinophils

  18. Mast Cell Synthesis of Mediators • Leukotrienes • Product of arachidonic acid from mast cell membranes • Similar effects to histamine in later stages • Prostaglandins • Similar effects to leukotrienes; they also induce pain • Platelet-activating factor • Similar effect to leukotrienes and platelet activation

  19. Mast Cells

  20. Mast Cells

  21. Mast Cells

  22. Phagocytosis • Process by which a cell ingests and disposes of foreign material • Production of adhesion molecules • Margination (pavementing) • Adherence of leukocytes to endothelial cells • Diapedesis • Emigration of cells through the endothelial junctions

  23. Phagocytosis

  24. Phagocytosis • Steps • Opsonization, recognition, and adherence • Engulfment • Phagosome formation • Fusion with lysosomal granules • Destruction of the target

  25. Phagocytes • Neutrophils • Also referred to as polymorphonuclear neutrophils (PMNs) • Predominate in early inflammatory responses • Ingest bacteria, dead cells, and cellular debris • Cells are short lived and become a component of the purulent exudate

  26. Phagocytes • Monocytes and macrophages • Monocytes are produced in the bone marrow, enter the circulation, and migrate to the inflammatory site, where they develop into macrophages • Macrophages typically arrive at the inflammatory site 3 to 7 days after neutrophils • Macrophage activation results in increased size, plasma membrane area, glucose metabolism, number of lysosomes, and secretory products

  27. Monocytes and Macrophages

  28. Phagocytes • Eosinophils • Mildly phagocytic • Duties • Defense against parasites and regulation of vascular mediators

  29. Phagocytes • Natural killer (NK) cells • Function is to recognize and eliminate cells infected with viruses and some function in eliminating cancer cells • Platelets • Activation results in degranulation and interaction with components of the coagulation system

  30. Cytokines • Interleukins • Produced primarily by macrophages and lymphocytes in response to a pathogen or stimulation by other products of inflammation • Many types • Examples • IL-1 is a proinflammatory cytokine • IL-10 is an anti-inflammatory cytokine

  31. Cytokines • Interferon • Protects against viral infections • Produced and released by virally infected host cells in response to viral double-stranded RNA • Types • IFN-alpha and IFN-beta • Induce production of antiviral proteins • IFN-gamma • Increases microbiocidal activity of macrophages

  32. Cytokines

  33. Cytokines • Tumor necrosis factor–alpha • Secreted by macrophages in response to PAMP and toll-like receptor recognition • Induces fever by acting as an endogenous pyrogen • Increases synthesis of inflammatory serum proteins • Causes muscle wasting (cachexia) and intravascular thrombosis

  34. Cytokines

  35. Local Manifestations of Inflammation • Results from vascular changes and corresponding leakage of circulating components into the tissue • Heat • Redness • Swelling • Pain

  36. Exudative Fluids • Serous exudate • Watery exudate: indicates early inflammation • Fibrinous exudate • Thick, clotted exudate: indicates more advanced inflammation • Purulent exudate • Pus: indicates a bacterial infection • Hemorrhagic exudate • Exudate contains blood: indicates bleeding

  37. Systemic Manifestations of Inflammation • Fever • Caused by exogenous and endogenous pyrogens • Act directly on the hypothalamus • Leukocytosis • Increased numbers of circulating leukocytes • Increased plasma protein synthesis • Acute-phase reactants • C-reactive protein, fibrinogen, haptoglobin, amyloid, ceruloplasmin, etc.

  38. Chronic Inflammation • Inflammation lasting 2 weeks or longer • Often related to an unsuccessful acute inflammatory response • Other causes of chronic inflammation: • High lipid and wax content of a microorganism • Ability to survive inside the macrophage • Toxins • Chemicals, particulate matter, or physical irritants

  39. Chronic Inflammation

  40. Chronic Inflammation • Characteristics • Dense infiltration of lymphocytes and macrophages • Granuloma formation • Epithelioid cell formation • Giant cell formation

  41. Resolution and Repair • Regeneration • Resolution • Returning injured tissue to the original structure and function • Repair • Replacement of destroyed tissue with scar tissue • Scar tissue • Composed primarily of collagen to restore the tensile strength of the tissue

  42. Resolution and Repair • Débridement • Cleaning up the dissolved clots, microorganisms, erythrocytes, and dead tissue cells • Healing • Filling in the wound • Sealing the wound (epithelialization) • Shrinking the wound (contraction)

  43. Healing • Primary intention • Wounds that heal under conditions of minimal tissue loss • Secondary intention • Wounds that require a great deal more tissue replacement • Open wound

  44. Healing • Reconstructive phase • Fibroblast proliferation • Collagen synthesis • Epithelialization • Contraction • Myofibroblasts • Cellular differentiation

  45. Healing • Maturation phase • Continuation of cellular differentiation • Scar tissue formation • Scar remodeling

  46. Healing

  47. Dysfunctional Wound Healing • Dysfunction during inflammatory response • Hemorrhage • Fibrous adhesion • Infection • Excess scar formation • Wound sepsis • Hypovolemia • Hypoproteinemia • Anti-inflammatory steroids

  48. Dysfunctional Wound Healing • Dysfunctional during reconstructive phase • Impaired collagen matrix assembly • Keloid scar • Hypertrophic scar • Impaired epithelialization • Anti-inflammatory steroids, hypoxemia, and nutritional deficiencies • Impaired contraction • Contracture

  49. Dysfunctional Wound Healing

  50. Dysfunctional Wound Healing • Wound disruption • Dehiscence • Wound pulls apart at the suture line • Excessive strain and obesity are causes • Increases risk of wound sepsis

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